Multiple myeloma (MM) cells express certain tumor-associated antigens that could serve as targets for active specific immunotherapy (ASI). The DF3/MUC1 glycoprotein is attractive as a potential target for ASI in that this antigen is recognized by cytotoxic T cells (CTLs) in patients with certain tumors. MM cells express DF3/MUC1 and CTLs from MM patients specifically recognize DF3/MUC1 epitopes. MM cells also express idiotypic (Id) structures on surface immunoglobulins. Studies of MM have detected antibodies and CTLs that exhibit specific recognition of the idiotypic antigen. These findings have suggested that DF3/MUC1 and Id epitopes could be exploited in the activation and stimulation of immunity against MM cells. The proposed work will in part study the development of ASI for MM using a recombinant vaccinia virus containing the MUC1 gene (rV-MUC1). Transgenic mice that express DF3/MUC1 in normal tissues will be immunized with rV-MUC1 and evaluated for induction of immunity against this antigen. A model of MM in the transgenic strain will be used to evaluated anti- tumor activity. Other mouse MM models will be studied to evaluate vaccinations with fusions of dendritic cells (DC) and MM cells. DC are the most potent antigen presenting cell. Fusion cells derived from DC and tumor have recently been shown to induce anti-tumor immunity. The effectiveness of the fusion cells as a vaccine for MM will be evaluated in the treatment of established disease. The preclinical studies will serve as the basis for Phase I/II studies of rV-MUC1 in the therapy of MM. Fusions of DC and MM cells will also be studied in a Phase I/II vaccine trial designed to define toxicity and induction of immune response. These trials will provide data from which studies can be designed to test whether development of ASI against MM-associated antigens improve the survival of patients with this disease. The Specific Aims are: 1) to induce active specific immunotherapy against multiple myeloma in preclinical models using recombinant vaccinia viruses and dendritic/multiple myeloma cell fusions as vaccines; 2) to perform a Phase I study of rV-MUC1 in patients with multiple myeloma; and 3) to perform a Phase I study of dendritic and myeloma cell fusions as vaccines in the treatment of multiple myeloma.